Preventing permanent brain injury after stroke

James D. Lechleiter, PhD, with Deborah Holstein, senior research associate, and doctoral graduate student Damian Lozano viewing a computer monitor in a lab.
James D. Lechleiter, PhD, with Deborah Holstein, senior research associate, and doctoral graduate student Damian Lozano.

An accidental discovery

By Michael Seringer

In the early 2000s, James Lechleiter’s lab at UT Health San Antonio was doing basic research focused on astrocytes, the star-shaped cells that do everything from managing neurotransmitters to clearing debris to regulating blood flow in the brain.

“We thought we had a drug candidate for brain cancer that would sensitize the cells to cell death, and in fact, the exact opposite happened,” Lechleiter said. “We added the drug and they were more resistant to cell death. That was surprising because we had done a lot of these same experiments with other cell types, like kidney cells, but when we got into the brain and this special astrocyte subtype, we got the surprising opposite result.”

James Donald Lechleiter, PhD

Professor of Cell Systems and Anatomy; Director of the Optical Imaging Core
Company: Astrocyte Pharmaceuticals Inc. (private)
Compound: Novel, small molecule — AST-004
Indication: Stroke, traumatic brain injury, neurodegenerative disease
Stage: Completed European clinical trial application; FDA investigational new drug application expected in 2023. Currently in Phase 1 human safety trials (Europe)
Funding: $20 million from company formation to clinical Phase 1 human trials, including grants, angel investors
Drug development requires a multidisciplinary team with experience navigating the complex and nuanced processes for advancing pharmaceutical compounds.

Lechleiter initially assumed the research team had made mistakes during the experiment, so his lab retested several times, all with the same result. Lechleiter knew he had a potential novel finding, and he has spent the last 16 years investigating it.

The mouse models used to test Lechleiter’s novel compound immediately showed encouraging results. Researchers observed a 50% reduction in stroke lesion size after the mice were treated with the drug. The drug’s therapeutic promise prompted UT Health San Antonio’s Office of Technology Commercialization to protect the intellectual property by filing for a patent. In 2013, the patent for AST-004 was granted, which made possible the formation of Astrocyte Pharmaceuticals Inc. out of Lechleiter’s lab in San Antonio.

Once Astrocyte Pharmaceuticals was formed, the search began for an industry insider with experience in the business of drug development. The importance of this step can’t be overstated. Successful companies require both good science and good business. Lechleiter and UT Health San Antonio were fortunate to find William Korinek, PhD, to fill the role of CEO for Astrocyte Pharmaceuticals in 2014. Korinek is a veteran from pharmaceutical giant Pfizer who recognized the potential of the compound, and over a period of four months worked on a business plan with Lechleiter.

Industrializing the drug

Moving from early laboratory successes to a pharmaceutical program ready for human clinical studies requires many complex steps. For AST-004, the team needed to demonstrate the drug worked in larger animals that have brains more similar to humans such as pigs and non-human primates. Substantial quantities of the drug (kilograms) needed to be manufactured under stringent good manufacturing practice conditions.

The maximum tolerated doses also needed to be identified in good laboratory practice toxicology studies. And because the first form of AST-004 is delivered intravenously, the process of developing the injectable formulation, filling the drug product vials and manufacturing the vials and the associated parts was challenging.

“We are really fortunate that AST-004 is a well-behaved small molecule that was fairly easy to synthesize and manufacture, with only some tweaking of the recipe to get the optimal pH and solubility,” Korinek said. “Overall, while the rigorous preclinical activities take considerable time and resources, the manufacturing and animal toxicology studies have gone smoothly. We were able to go up to a very high dose in the safety studies, which gives us confidence that we have a very safe molecule, and we now have over a thousand vials ready for the human clinical studies.”

Lechleiter believes the synthesis, formulation and manufacturing went well because his team hired a pharmaceutical chemist with 30 years of experience developing drug compounds.

“Getting someone who is really specialized and has a lot of experience in chemistry, formulation and manufacturing is crucial to be successful and make it go more smoothly,” Lechleiter said, explaining that drug development requires a multidisciplinary team with experience navigating the complex and nuanced processes for advancing pharmaceutical compounds.

“Get someone who has done this before. Don’t try to do it on your own. Seek advice from experts and be sure to document everything you have done,” Lechleiter said. “It’s a long process. That’s why you need people who are specialists in different areas and know what to expect. All the steps take time and a lot of resources.”

Funding a multidisciplinary team

While large-animal efficacy research, compound manufacturing and animal safety studies went smoothly, they are also expensive, and Lechleiter and Korinek had to raise enough funds to conduct specialized research. To increase investor confidence that the drug would work in the larger and more complex human brain, the research team conducted studies in the more expensive pig and primate models. Astrocyte Pharmaceuticals relied on grants and an angel investor group to provide the necessary financing.

“We first focused on applying for a small business grant and were successful in securing a $700,000 [National Institutes of Health] grant in the first year of the company,” said Lechleiter. “That was a key scientific stamp of approval from independent scientists confirming this was exciting research, which was really crucial to gaining the confidence and interest of angel investor networks.”

Over the eight years since its founding, Astrocyte Pharmaceuticals raised and spent $15 million to get through animal trials and preclinical studies and another $5 million to conduct the human Phase 1 clinical trials.

Additional patents

The company’s research surrounding Lechleiter’s early discoveries has resulted in multiple additional patents, including patents on using the drug to treat a variety of central nervous system indications. They also patented different molecular structures that might further improve upon the original compound and improved methods to synthesize the molecule in fewer steps, making the drug easier and cheaper to produce.

AST-004 holds promise for multiple indications. During animal studies funded by a Department of Defense grant to investigate the drug’s therapeutic effect on blast traumatic brain injuries, the team discovered another possible indication for the drug. During the DOD research, Jun Hee Kim, PhD, UT Health San Antonio professor in the Department of Cellular and Integrative Physiology — who has an office next door to Lechleiter’s lab — suggested the lab test the hearing of the mice subjected to explosions.

The mice treated with AST-004 had almost no hearing loss after the blast test, but those mice that had not been treated with AST-004 experienced significant hearing loss.

“It turns out the inner ear has a lot of the same neural structure as the brain,” Lechleiter said. “The receptor subtype that we are targeting is richly expressed in the inner ear. We think the same mechanism is at play. We just weren’t looking for it.”

“We went into this research thinking only about traumatic brain injury and stroke, but because of how the molecule is fundamentally affecting cell health and recovery in the brain, it turns out there are a lot of other indications with neuronal stress where there could be significant benefits,” Lechleiter said. “We’ve now seen positive data with noise-induced hearing loss, Alzheimer’s disease, inflammatory pain and other areas. AST-004 appears to be activating a central neuroprotective pathway that we believe can be broadly used to help millions and millions of patients.”

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